Presenting Characteristics, Treatment, and Visual Outcomes in Streptococcal Compared to Non-Streptococcal Endophthalmitis

Purpose: Report the clinical findings, risk factors, treatment, and visual outcomes associated with Streptococcus endophthalmitis in comparison to culture-positive endophthalmitis associated with non-Streptococcus species. Methods: A retrospective chart review of adults between 18 and 89 years of age diagnosed with exogenous culture-positive endophthalmitis between January 1, 2009, and January 1, 2018, at the Duke Eye Center (Durham, North Carolina) with at least six months of follow-up from time of initial diagnosis was conducted. Clinical data including patient demographics, ocular history, baseline corrected visual acuity (VA) prior to presentation, time to presentation, presenting exam findings, VA at presentation, presumed etiology of endophthalmitis, medical and surgical management, and VA at the six-month follow-up was extracted and statistically analyzed. Results: Fifty-six eyes from 56 patients with culture-positive endophthalmitis were identified. Eyes with Streptococcus (n=18) had elevated intraocular pressure (IOP) at presentation (p=0.002), worse mean VA (Snellen) at presentation (20/14159 vs. 20/3098, p<0.001), and worse mean VA (Snellen) at six months (20/3475 vs. 20/235, p<0.001) compared to non-Streptococcus cases (n=38). Time to presentation (days) (median, IQR) was longer in eyes that underwent glaucoma surgery for both Streptococcus (2241 (836, 3709) vs. 3 (2, 31), p=0.003) and non-Streptococcus endophthalmitis (1236 (125, 3582) vs. 6 (4, 25), p<0.0001). There was no difference in VA at six months between Streptococcus and non-Streptococcus eyes based on treatment. Conclusions: Streptococci are rare but important causes of exogenous endophthalmitis, and in our study, they were associated with worse visual outcomes than non-Streptococci. A history of any glaucoma surgery, even procedures performed years earlier, should be elicited when evaluating patients with ocular symptoms.


Introduction
Endophthalmitis is a medical and ophthalmic emergency that requires suspicion on the part of clinicians to ensure prompt recognition, referral, and treatment.The etiology of endophthalmitis can be categorized as exogenous, when bacteria directly enter the eye via trauma, iatrogenic activity, or extension of corneal infection, or as endogenous, resulting from hematogenous spread of bacteria or fungi to the eye.Cases of culture-positive bacterial endophthalmitis are more commonly due to exogenous causes.Both categories of endophthalmitis can lead to severe visual loss.
Among bacterial causes of endophthalmitis, prior studies have suggested that endophthalmitis due to Streptococcus pneumoniae is clinically more severe, is associated with worse visual outcomes, and carries a higher risk of evisceration or enucleation compared to endophthalmitis caused by non-Streptococcus organisms [1].Coagulase-negative Staphylococci and viridans streptococci, while generally less virulent than S. pneumoniae, cause most cases of post-intravitreal injection endophthalmitis and post-cataract surgery endophthalmitis [2,3].Other non-Streptococcus bacteria implicated as the causative organism in exogenous endophthalmitis include Haemophilus influenzae, Enterococcus, and Bacillus species.
To the best of our knowledge, only one prior study has compared Streptococcus to non-Streptococcus culturepositive bacterial endophthalmitis.In a series of 47 cases of culture-positive bacterial endophthalmitis, endophthalmitis caused by Streptococcus species was associated with a worse final visual acuity (VA)

Statistical analysis
Statistical analysis was performed using Stata (StataCorp.2021.Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC).Categorical variables were compared using Pearson's Chi-squared test.Continuous variables for two sample groups normally distributed were compared using a two-tailed t-test and continuous variables for two sample groups not normally distributed were compared using Wilcoxon Rank Sum.Logistic regression analysis was used to identify associations between binary outcomes and continuous predictor variables.Snellen-equivalent VA was converted to the logarithm of the minimum angle of resolution (logMAR) for the purpose of statistical comparison.The logMAR equivalents of count fingers, hand motion, light perception (LP), and no light perception (NLP) were 2.3, 2.6, 2.9, and 3.2, respectively, as extrapolated from a previous study for measurement at one foot [5].A p-value less than 0.05 was used in all analyses to define statistical significance.

Clinical characteristics and bacterial species
Fifty-six patients with unilateral exogenous culture-positive endophthalmitis were identified.The mean age was 67 years (range: 30-85 years).Eighteen patients had positive ocular cultures for Streptococcus and 38 for non-Streptococcus species.There were no significant differences in age or sex between the two groups (Table 1).

Causative etiologies
The etiologies for the 56 cases of culture-positive endophthalmitis included cataract surgery (15/
All 18 patients with Streptococcus were treated with intravitreal injection of vancomycin on presentation, and 17/18 (94%) were also treated with intravitreal ceftazidime.Similarly, all non-Streptococcus patients were treated with intravitreal vancomycin on presentation, and 32/38 (84%) were also treated with intravitreal ceftazidime.
Topical prednisolone acetate 1% was initiated on presentation in 14/18 (78%) patients with Streptococcus and of these patients, 7/14 (50%) also received an oral steroid.Among patients with Streptococcus endophthalmitis, there was no difference in change in VA from the time of presentation to the six-month follow-up for patients treated with topical steroids compared to patients treated with both topical and oral steroids (p=0.069).Three patients did not receive any topical or oral steroids and one patient received oral steroids only.

Discussion
An important finding from our study is that time to presentation was longer in patients with culturepositive Streptococcus endophthalmitis and patients with non-Streptococcus endophthalmitis that had undergone glaucoma surgery (trabeculectomy or GDD implant) compared to patients that had not undergone glaucoma surgery.Delayed presentation (> one month after surgery) of endophthalmitis following glaucoma surgery has been previously reported [6][7][8][9].In a series of four eyes with culture-positive endophthalmitis following GDD implant, one eye developed endophthalmitis 24 months after GDD implant [6].In a series of 53 eyes with delayed onset endophthalmitis following trabeculectomy, the mean time to onset of endophthalmitis was 64 months (SD: 46 months) [7].Eyes presenting with endophthalmitis more than 10 years after trabeculectomy or GDD have been reported [8,9].Our results for median time to presentation with endophthalmitis due to Streptococcus and non-Streptococcus species following glaucoma surgery are consistent with these published studies.
To our knowledge, there are no published reports comparing the time to presentation of culture-positive endophthalmitis following glaucoma surgery with culture-positive endophthalmitis following other inciting etiologies.In contrast, our results demonstrated patients with endophthalmitis culture-positive for Streptococcus species and patients with endophthalmitis culture-positive for non-Streptococcus species have a longer time to presentation following glaucoma surgery compared to other inciting etiologies.These results suggest a history of any glaucoma surgery, even procedures performed years earlier, should be elicited when evaluating patients with ocular symptoms.While our study size did not allow for stratification of results for time to presentation by type of glaucoma surgery, e.g., trabeculectomy or GDD implant, reporting results as time to presentation following "glaucoma surgery" acknowledges patients may not recall the specific type of glaucoma surgery they underwent months or years later.
Delayed presentation of endophthalmitis following glaucoma surgery can be attributed to the inherent characteristics of the surgical procedure.During trabeculectomy, a defect is intentionally created in the eye wall.This defect allows aqueous fluid to filter into the subconjunctival space, forming an elevated blister known as a filtering bleb.In this area, the normal barrier provided by the eye wall is compromised or lost.It is hypothesized that after trabeculectomy, because only the conjunctiva separates ocular surface flora from the aqueous humor at the trabeculectomy site, causative organisms may migrate across the conjunctival epithelium into the anterior chamber of the eye and lead to endophthalmitis months or years after trabeculectomy surgery [10].Delayed onset endophthalmitis associated with GDD implants may be due to bacterial migration from the surface of the eye following erosion and exposure of the drainage device itself [6].The role of GDD erosion in the etiology of post-GDD implant endophthalmitis is shown by the rarity of endophthalmitis following GDD implant without tube shunt erosion [11].
Another unique feature of our study was comparing ocular exam characteristics at the time of presentation of endophthalmitis in patients culture-positive for Streptococcus with patients culture-positive for non-Streptococcus species.Our results demonstrated IOP at presentation was elevated in eyes with Streptococcus endophthalmitis compared to non-Streptococcus endophthalmitis.Previous reports of elevated IOP at the time of presentation of endophthalmitis have been limited to the setting of endophthalmitis following trabeculectomy [7,12].Findings from our study expand beyond trabeculectomy-related endophthalmitis to show that IOP at the time of presentation of culture-positive endophthalmitis due to Streptococcus species was associated with a range of inciting etiologies.
Elevated IOP at the time of presentation of endophthalmitis may be due to inflammation of the trabecular meshwork, or inflammatory debris trapped in the trabecular meshwork, similar to the proposed mechanism of elevated IOP in inflammatory ocular hypertension syndrome [13].A greater inflammatory response triggered by streptococcal exotoxins and enzymes, and the subsequent effect of this inflammation on the trabecular meshwork, may explain our results demonstrating elevated IOP at the time of presentation of endophthalmitis culture-positive for Streptococcus species [14].
Endophthalmitis was more likely to be culture-positive for Streptococcus species compared to non-Streptococcus species following open globe injury in our study.Most cases of post-traumatic endophthalmitis are caused by bacteria present in the environment.Risk factors for developing posttraumatic endophthalmitis include delayed globe closure, trauma in a rural setting, wound contamination, presence of an intraocular foreign body (IOFB), and lens capsule disruption [15].In a series of 565 bacterial isolates from 581 eyes with endophthalmitis following open globe injury, the most common isolate was Bacillus species, followed by S. pneumonia and coagulase-negative Staphylococci [16].Bacillus species are commonly found in cases of post-traumatic endophthalmitis with IOFB or soil contamination [17].An explanation for our finding of greater odds of isolating Streptococcus species compared to non-Streptococcus species from patients with culture-positive endophthalmitis following open globe injury is that no eyes with open globe injury in our study had an IOFB.
Endophthalmitis was also more likely to be culture-positive for Streptococcus rather than non-Streptococcus species in the setting of trabeculectomy in our study.This is consistent with a previously reported series of 38 eyes with endophthalmitis caused by Streptococcus species, where the most common clinical setting was post-glaucoma surgery, in particular trabeculectomy [18].Similarly, in a series of 39 eyes that developed culture-positive endophthalmitis after trabeculectomy, the most frequently isolated organisms were Streptococcus species [19].A possible explanation for our results finding greater odds of isolating Streptococcus species compared to non-Streptococcus species in patients with endophthalmitis following trabeculectomy is that, unlike Streptococci, Staphylococci do not produce exotoxins and may not have the ability to penetrate intact conjunctiva [20].
Endophthalmitis culture-positive for Streptococcus species was associated with poorer VA at presentation and at six months compared to endophthalmitis culture-positive for non-Streptococcus species in our study.
Greater than 50% of patients with Streptococcus endophthalmitis in our study had poor VA (NLP or LP) at the time of presentation and at six months.These results are consistent with other studies showing poor visual outcomes associated with culture-positive Streptococcus endophthalmitis despite prompt and appropriate treatment.In a series of 63 eyes treated for endophthalmitis due to Streptococcus species, the mean Snellen VA at presentation was 20/4900 (equivalent to hand motion VA), improving to 20/2900 at follow-up [21].The severe impact of S. pneumoniae endophthalmitis on VA outcome was demonstrated in a study of 38 eyes treated for S. pneumoniae endophthalmitis where the final VA was NLP in 30/38 (79%) [1].
The reasons why patients with culture-positive Streptococcus endophthalmitis have poor visual outcomes compared to other etiologic bacteria are not fully understood.Studies of a capsule-deficient strain of S. pneumoniae in rabbits showed endophthalmitis caused by the encapsulated strain is more damaging to retinal function than the capsule-deficient strain, suggesting the capsule is an important virulence factor in endophthalmitis [22].Additionally, the S. pneumoniae toxin pneumolysin creates a virulence factor that causes damage as a pore-forming toxin and may mediate inflammation through activation of the classical complement pathway [23].However, a study of streptococcal-specific virulence factors in eyes with culturepositive Streptococcus endophthalmitis found no association between the presence of pneumolysin, autolysin, and hyaluronidase and visual outcome or rate of enucleation [18].While antibiotics kill intraocular organisms, they do not directly affect the toxins or enzymes that mediate inflammation and adversely affect retinal function [24].These findings suggest any number of factors related to the characteristics of Streptococci, either individually or in combination, may contribute to the poor VA outcomes associated with endophthalmitis due to Streptococcus species despite treatment.

Limitations
Limitations of the current study include its retrospective design and relatively small number of patients.However, the frequency of cases in this study, 56 eyes over a nine-year period, fits with another published series of culture-positive endophthalmitis from a single institution where 47 cases of culture-positive bacterial endophthalmitis over 12 years were reported [4].Regarding management, our study did not attempt to analyze antibiotic susceptibility patterns due to limited susceptibility data.However, as a singlecenter study, the management of cases was largely homogenous, and patients did not come from a wide geographic area with potentially different patterns of antibiotic resistance, minimizing the impact on outcomes.

Conclusions
Streptococci are rare but important causes of exogenous endophthalmitis, and in our study, they were associated with worse visual outcomes than non-Streptococci.Endophthalmitis was more likely to be culturepositive for Streptococcus species rather than non-Streptococcus species in the setting of open globe injury and trabeculectomy (glaucoma filtration surgery).Time to presentation was longer in patients with culturepositive Streptococcus endophthalmitis and non-Streptococcus endophthalmitis that had undergone glaucoma surgery (trabeculectomy or GDD implant) compared to patients with culture-positive endophthalmitis following other inciting etiologies.A history of any glaucoma surgery, even procedures performed years earlier, should be elicited when evaluating patients with ocular symptoms.While our study had limited power, we did not see any effect of the use of adjunctive corticosteroids.Prompt antimicrobial therapy and intervention are key to optimizing outcomes among patients with culture-positive bacterial

TABLE 3 : Distribution of causative etiologies of culture-positive endophthalmitis.
a: none with IOFB; b: intravitreal injection; c: partial or full thickness; d: cataract surgery without intracameral antibiotics; e: PPV; f: GDD PPV, pars plana vitrectomy; GDD, glaucoma drainage device; IOFB, intraocular foreign bodyPresentationWhen compared to non-Streptococcus cases, Streptococcus endophthalmitis was significantly associated with initial exam findings of conjunctival hyperemia, elevated intraocular pressure (IOP), and increased anterior chamber fibrin (Table1).There was no difference in baseline VA prior to presentation between patients with Streptococcus compared with non-Streptococcus endophthalmitis (p=0.72)(Table4).Eyes with Streptococcus had worse mean VA (Snellen) at presentation compared to non-Streptococcus cases (20/14159 vs. 20/3098, p<0.001).At presentation, 13/18 (72%) of patients with Streptococcus had NLP or LP VA in the affected eye compared with 5/38 (13%) of patients with non-Streptococcus (p<0.001).Overall, there was no difference in time to presentation (days) (median, IQR) comparing patients with positive ocular cultures for Streptococcus to patients with positive ocular cultures for non-Streptococcus bacteria (Table4).However, patients with a positive ocular culture for Streptococcus and a history of glaucoma surgery (trabeculectomy or GDD) had a longer time to presentation (days) (median, IQR) compared to patients with Streptococcus who did not undergo glaucoma surgery (2241 (836, 3709) vs. 3 (2, 31) p=0.003).Similarly, patients with a positive ocular culture for non-Streptococcus species and a history of glaucoma surgery (trabeculectomy or GDD) had a longer time to presentation (days) (median, IQR) compared to patients culture-positive for non-Streptococcus species who did not undergo glaucoma surgery (1236 (125, 3582) vs. 6 (4, 25), p<0.0001)).

TABLE 4 : VA for culture-positive Streptococcus and non-Streptococcus endophthalmitis.
Continuous variables for two sample groups normally distributed were compared using a two-tailed t-test and continuous variables for two sample groups not normally distributed were compared using Wilcoxon Rank Sum.Categorical variables were compared using Pearson's Chi-squared test.A p-value less than 0.05 was used in all analyses to define statistical significance.